DESCRIPTION: (from applicant's abstract) Modulation of the voltage-dependent calcium channels regulating release by neurotransmitters is likely to be a common mechanism of regulating synaptic plasticity. There is currently no consensus on the identity of the calcium channel controlling neurotransmitter release, thus raising the possibility that different synapses may use different channel types. This project exploits the well characterized circuitry of the hippocampus to investigate the identity of calcium channels controlling release in specific inhibitory synapses, and also the modulation of these channels by neurotransmitter. The inhibitory synapses between the CA1 pyramidal cells and the vertical cells of the stratum oriens/alveus, the basket cells in the stratum pyramidale, and the stellate cells in the stratum laciunosum/moleculare will be studied. The vertical and basket cells mediate both feedforward and recurrent inhibition primarily by activation of GABAA receptors. The stellate mediate feedforward inhibition by activation of GABAB receptors. The first specific aim is to provide thorough characterization of the voltage-dependent calcium channels in the presynaptic cells of each of these synapses, using whole cell voltage-clamp recording in dissociated cells. The data obtained in these experiments will provide a foundation for the subsequent studies in neurotransmitter release and modulation of calcium channels. The second specific aim is to determine which calcium channel type controls release in each of the synapses in question, by application of specific calcium channel antagonists during whole cell voltage clamp recording in the postsynaptic cell in hippocampal slice preparation. The final specific aim is to determine if a decrease in calcium influx can account for the decrease of inhibitory synaptic transmission produced by activation of presynaptic GABAB and mu opioid receptors. The effect of GABA and opiates on calcium currents will be studied using whole cell voltage clamp recording in dissociated vertical, basket and stellate interneurons and the involvement of specific G proteins in this process will be explored. Understanding how neurotransmitter regulate specific synapses by modulation of distinct calcium channels types will provide insight into some of the mechanisms of synaptic plasticity. In addition, these studies will provide a better foundation for pharmaceutical therapies in diseases such as epilepsy and neurodegeneration where the use of neuromodulators is being actively pursued. Moreover, this information will also provide insights into the cellular pathology of various neuronal disorders in which synaptic function is altered.